I have found that mouse mammary tumors demonstrate a remarkable preference for growth in their natural anatomic site, the mammary fatpad. Furthermore, mouse mammary tumors were found to metastasize more readily from the mammary fatpad than from subcutaneous sites. I have shown that immunological mechanisms do not adequately explain these observed site effects on tumor growth and metastasis and have focused on intraepithelial and stromal-epithelial cellular interactions as alternative mechanisms. Interactive homeostatic mechanisms occur between cells from the time of blastlal formation. These regulatory processes are usually able to maintain tissue integrity throughout life and can be regarded as mechanisms of "non-immune surveillance" against neoplasia. In the mouse, normal mammary gland tissue interactions can be demonstrated as early as in the 11\day (in utero) fetal mammary bud, in the virgin female, during pregnancy/lactation related glandular remodeling, between mammary epithelium and preneoplastic mammary tissues, and, as I have shown, between normal mammary gland tissues and malignant mammary tissues. Manipulation of tissue interactions could lead to new therapeutic strategies against cancer growth and progression. I have developed mammary tumor lines with drug resistance markers and have utilized these to study metabolic cooperation between mammary tissues. I have adapted the three-dimensional culture system in collagen gel to study tissue interactions in vitro, and I have begun to utilize embryonic tissues as a defined source of functional mammary mesechyme to study epithelial-mesenchymal interactions with mammary tumor cells. These new tools will aid my continuing investigations of mammary tumors growing in their natural anatomic site to determine both the mechanisms of site preference and their consequences. The study of mechanism will continue to focus on cellular interactions within the mammary gland fatpad. The studies of the consequences will focus on the affect of mammary gland tissue interactions on neoplastic progression. My experimental approaches are based on the principles that cell shape, tissue architecture, the extracellular matrix, and both stromal-epithelial and intraepithelial interactions may all play significant roles in the normal growth and development of the mammary gland.